title: Magnetic resonance T1 relaxation time of venous thrombus is determined by iron processing and predicts susceptibility to lysis.
abstract: BACKGROUND
  The magnetic resonance longitudinal relaxation time (T1) changes with thrombus age in humans. In this study, we investigate the possible mechanisms that give rise to the T1 signal in venous thrombi and whether changes in T1 relaxation time are informative of the susceptibility to lysis.
  
  
  RESULTS
  Venous thrombosis was induced in the vena cava of BALB/C mice, and temporal changes in T1 relaxation time correlated with thrombus composition. The mean T1 relaxation time of thrombus was shortest at 7 days following thrombus induction and returned to that of blood as the thrombus resolved. T1 relaxation time was related to thrombus methemoglobin formation and further processing. Studies in inducible nitric oxide synthase (iNOS(-/-))-deficient mice revealed that inducible nitric oxide synthase mediates oxidation of erythrocyte lysis-derived iron to paramagnetic Fe3+, which causes thrombus T1 relaxation time shortening. Studies using chemokine receptor-2-deficient mice (Ccr2(-/-)) revealed that the return of the T1 signal to that of blood is regulated by removal of Fe3+ by macrophages that accumulate in the thrombus during its resolution. Quantification of T1 relaxation time was a good predictor of successful thrombolysis with a cutoff point of <747 ms having a sensitivity and specificity to predict successful lysis of 83% and 94%, respectively.
  
  
  CONCLUSIONS
  The source of the T1 signal in the thrombus results from the oxidation of iron (released from the lysis of trapped erythrocytes in the thrombus) to its paramagnetic Fe3+ form. Quantification of T1 relaxation time appears to be a good predictor of the success of thrombolysis.
authors.affiliation: Academic Department of Surgery, Cardiovascular Division, Kings College London, BHF Centre of Research Excellence & NIHR Biomedical Research Centre at Kings Health Partners, St Thomas' Hospital, London, UK (P.S., B.M., J.H., A.S.P., C.E.E., K.M., S.P.G., A.A., O.T.L., R.Q.A., S.P., M.W., A.S.); Division of Imaging Sciences and Biomedical Engineering, Kings College London, BHF Centre of Research Excellence & Wellcome Trust - EPSRC Medical Engineering Centre & NIHR Biomedical Research Centre at Kings Health Partners, St. Thomas' Hospital, London, UK (M.E.A., U.B., A.P., A.J.W., T.S.); Radiology Department, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile (M.E.A.); Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital Solna, Stockholm, Sweden (T.R.); and Philips Healthcare, Guildford, UK (A.J.W.).
authors.forename: Prakash
authors.initials: P
authors.lastname: Saha
authors.affiliation: Academic Department of Surgery, Cardiovascular Division, Kings College London, BHF Centre of Research Excellence & NIHR Biomedical Research Centre at Kings Health Partners, St Thomas' Hospital, London, UK (P.S., B.M., J.H., A.S.P., C.E.E., K.M., S.P.G., A.A., O.T.L., R.Q.A., S.P., M.W., A.S.); Division of Imaging Sciences and Biomedical Engineering, Kings College London, BHF Centre of Research Excellence & Wellcome Trust - EPSRC Medical Engineering Centre & NIHR Biomedical Research Centre at Kings Health Partners, St. Thomas' Hospital, London, UK (M.E.A., U.B., A.P., A.J.W., T.S.); Radiology Department, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile (M.E.A.); Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital Solna, Stockholm, Sweden (T.R.); and Philips Healthcare, Guildford, UK (A.J.W.).
authors.forename: Marcelo E
authors.initials: ME
authors.lastname: Andia
authors.affiliation: Academic Department of Surgery, Cardiovascular Division, Kings College London, BHF Centre of Research Excellence & NIHR Biomedical Research Centre at Kings Health Partners, St Thomas' Hospital, London, UK (P.S., B.M., J.H., A.S.P., C.E.E., K.M., S.P.G., A.A., O.T.L., R.Q.A., S.P., M.W., A.S.); Division of Imaging Sciences and Biomedical Engineering, Kings College London, BHF Centre of Research Excellence & Wellcome Trust - EPSRC Medical Engineering Centre & NIHR Biomedical Research Centre at Kings Health Partners, St. Thomas' Hospital, London, UK (M.E.A., U.B., A.P., A.J.W., T.S.); Radiology Department, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile (M.E.A.); Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital Solna, Stockholm, Sweden (T.R.); and Philips Healthcare, Guildford, UK (A.J.W.).
authors.forename: Bijan
authors.initials: B
authors.lastname: Modarai
authors.affiliation: Academic Department of Surgery, Cardiovascular Division, Kings College London, BHF Centre of Research Excellence & NIHR Biomedical Research Centre at Kings Health Partners, St Thomas' Hospital, London, UK (P.S., B.M., J.H., A.S.P., C.E.E., K.M., S.P.G., A.A., O.T.L., R.Q.A., S.P., M.W., A.S.); Division of Imaging Sciences and Biomedical Engineering, Kings College London, BHF Centre of Research Excellence & Wellcome Trust - EPSRC Medical Engineering Centre & NIHR Biomedical Research Centre at Kings Health Partners, St. Thomas' Hospital, London, UK (M.E.A., U.B., A.P., A.J.W., T.S.); Radiology Department, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile (M.E.A.); Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital Solna, Stockholm, Sweden (T.R.); and Philips Healthcare, Guildford, UK (A.J.W.).
authors.forename: Ulrike
authors.initials: U
authors.lastname: Blume
authors.affiliation: Academic Department of Surgery, Cardiovascular Division, Kings College London, BHF Centre of Research Excellence & NIHR Biomedical Research Centre at Kings Health Partners, St Thomas' Hospital, London, UK (P.S., B.M., J.H., A.S.P., C.E.E., K.M., S.P.G., A.A., O.T.L., R.Q.A., S.P., M.W., A.S.); Division of Imaging Sciences and Biomedical Engineering, Kings College London, BHF Centre of Research Excellence & Wellcome Trust - EPSRC Medical Engineering Centre & NIHR Biomedical Research Centre at Kings Health Partners, St. Thomas' Hospital, London, UK (M.E.A., U.B., A.P., A.J.W., T.S.); Radiology Department, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile (M.E.A.); Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital Solna, Stockholm, Sweden (T.R.); and Philips Healthcare, Guildford, UK (A.J.W.).
authors.forename: Julia
authors.initials: J
authors.lastname: Humphries
authors.affiliation: Academic Department of Surgery, Cardiovascular Division, Kings College London, BHF Centre of Research Excellence & NIHR Biomedical Research Centre at Kings Health Partners, St Thomas' Hospital, London, UK (P.S., B.M., J.H., A.S.P., C.E.E., K.M., S.P.G., A.A., O.T.L., R.Q.A., S.P., M.W., A.S.); Division of Imaging Sciences and Biomedical Engineering, Kings College London, BHF Centre of Research Excellence & Wellcome Trust - EPSRC Medical Engineering Centre & NIHR Biomedical Research Centre at Kings Health Partners, St. Thomas' Hospital, London, UK (M.E.A., U.B., A.P., A.J.W., T.S.); Radiology Department, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile (M.E.A.); Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital Solna, Stockholm, Sweden (T.R.); and Philips Healthcare, Guildford, UK (A.J.W.).
authors.forename: Ashish S
authors.initials: AS
authors.lastname: Patel
authors.affiliation: Academic Department of Surgery, Cardiovascular Division, Kings College London, BHF Centre of Research Excellence & NIHR Biomedical Research Centre at Kings Health Partners, St Thomas' Hospital, London, UK (P.S., B.M., J.H., A.S.P., C.E.E., K.M., S.P.G., A.A., O.T.L., R.Q.A., S.P., M.W., A.S.); Division of Imaging Sciences and Biomedical Engineering, Kings College London, BHF Centre of Research Excellence & Wellcome Trust - EPSRC Medical Engineering Centre & NIHR Biomedical Research Centre at Kings Health Partners, St. Thomas' Hospital, London, UK (M.E.A., U.B., A.P., A.J.W., T.S.); Radiology Department, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile (M.E.A.); Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital Solna, Stockholm, Sweden (T.R.); and Philips Healthcare, Guildford, UK (A.J.W.).
authors.forename: Alkystis
authors.initials: A
authors.lastname: Phinikaridou
authors.affiliation: Academic Department of Surgery, Cardiovascular Division, Kings College London, BHF Centre of Research Excellence & NIHR Biomedical Research Centre at Kings Health Partners, St Thomas' Hospital, London, UK (P.S., B.M., J.H., A.S.P., C.E.E., K.M., S.P.G., A.A., O.T.L., R.Q.A., S.P., M.W., A.S.); Division of Imaging Sciences and Biomedical Engineering, Kings College London, BHF Centre of Research Excellence & Wellcome Trust - EPSRC Medical Engineering Centre & NIHR Biomedical Research Centre at Kings Health Partners, St. Thomas' Hospital, London, UK (M.E.A., U.B., A.P., A.J.W., T.S.); Radiology Department, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile (M.E.A.); Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital Solna, Stockholm, Sweden (T.R.); and Philips Healthcare, Guildford, UK (A.J.W.).
authors.forename: Colin E
authors.initials: CE
authors.lastname: Evans
authors.affiliation: Academic Department of Surgery, Cardiovascular Division, Kings College London, BHF Centre of Research Excellence & NIHR Biomedical Research Centre at Kings Health Partners, St Thomas' Hospital, London, UK (P.S., B.M., J.H., A.S.P., C.E.E., K.M., S.P.G., A.A., O.T.L., R.Q.A., S.P., M.W., A.S.); Division of Imaging Sciences and Biomedical Engineering, Kings College London, BHF Centre of Research Excellence & Wellcome Trust - EPSRC Medical Engineering Centre & NIHR Biomedical Research Centre at Kings Health Partners, St. Thomas' Hospital, London, UK (M.E.A., U.B., A.P., A.J.W., T.S.); Radiology Department, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile (M.E.A.); Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital Solna, Stockholm, Sweden (T.R.); and Philips Healthcare, Guildford, UK (A.J.W.).
authors.forename: Katherine
authors.initials: K
authors.lastname: Mattock
authors.affiliation: Academic Department of Surgery, Cardiovascular Division, Kings College London, BHF Centre of Research Excellence & NIHR Biomedical Research Centre at Kings Health Partners, St Thomas' Hospital, London, UK (P.S., B.M., J.H., A.S.P., C.E.E., K.M., S.P.G., A.A., O.T.L., R.Q.A., S.P., M.W., A.S.); Division of Imaging Sciences and Biomedical Engineering, Kings College London, BHF Centre of Research Excellence & Wellcome Trust - EPSRC Medical Engineering Centre & NIHR Biomedical Research Centre at Kings Health Partners, St. Thomas' Hospital, London, UK (M.E.A., U.B., A.P., A.J.W., T.S.); Radiology Department, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile (M.E.A.); Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital Solna, Stockholm, Sweden (T.R.); and Philips Healthcare, Guildford, UK (A.J.W.).
authors.forename: Steven P
authors.initials: SP
authors.lastname: Grover
authors.affiliation: Academic Department of Surgery, Cardiovascular Division, Kings College London, BHF Centre of Research Excellence & NIHR Biomedical Research Centre at Kings Health Partners, St Thomas' Hospital, London, UK (P.S., B.M., J.H., A.S.P., C.E.E., K.M., S.P.G., A.A., O.T.L., R.Q.A., S.P., M.W., A.S.); Division of Imaging Sciences and Biomedical Engineering, Kings College London, BHF Centre of Research Excellence & Wellcome Trust - EPSRC Medical Engineering Centre & NIHR Biomedical Research Centre at Kings Health Partners, St. Thomas' Hospital, London, UK (M.E.A., U.B., A.P., A.J.W., T.S.); Radiology Department, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile (M.E.A.); Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital Solna, Stockholm, Sweden (T.R.); and Philips Healthcare, Guildford, UK (A.J.W.).
authors.forename: Anwar
authors.initials: A
authors.lastname: Ahmad
authors.affiliation: Academic Department of Surgery, Cardiovascular Division, Kings College London, BHF Centre of Research Excellence & NIHR Biomedical Research Centre at Kings Health Partners, St Thomas' Hospital, London, UK (P.S., B.M., J.H., A.S.P., C.E.E., K.M., S.P.G., A.A., O.T.L., R.Q.A., S.P., M.W., A.S.); Division of Imaging Sciences and Biomedical Engineering, Kings College London, BHF Centre of Research Excellence & Wellcome Trust - EPSRC Medical Engineering Centre & NIHR Biomedical Research Centre at Kings Health Partners, St. Thomas' Hospital, London, UK (M.E.A., U.B., A.P., A.J.W., T.S.); Radiology Department, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile (M.E.A.); Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital Solna, Stockholm, Sweden (T.R.); and Philips Healthcare, Guildford, UK (A.J.W.).
authors.forename: Oliver T
authors.initials: OT
authors.lastname: Lyons
authors.affiliation: Academic Department of Surgery, Cardiovascular Division, Kings College London, BHF Centre of Research Excellence & NIHR Biomedical Research Centre at Kings Health Partners, St Thomas' Hospital, London, UK (P.S., B.M., J.H., A.S.P., C.E.E., K.M., S.P.G., A.A., O.T.L., R.Q.A., S.P., M.W., A.S.); Division of Imaging Sciences and Biomedical Engineering, Kings College London, BHF Centre of Research Excellence & Wellcome Trust - EPSRC Medical Engineering Centre & NIHR Biomedical Research Centre at Kings Health Partners, St. Thomas' Hospital, London, UK (M.E.A., U.B., A.P., A.J.W., T.S.); Radiology Department, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile (M.E.A.); Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital Solna, Stockholm, Sweden (T.R.); and Philips Healthcare, Guildford, UK (A.J.W.).
authors.forename: Rizwan Q
authors.initials: RQ
authors.lastname: Attia
authors.affiliation: Academic Department of Surgery, Cardiovascular Division, Kings College London, BHF Centre of Research Excellence & NIHR Biomedical Research Centre at Kings Health Partners, St Thomas' Hospital, London, UK (P.S., B.M., J.H., A.S.P., C.E.E., K.M., S.P.G., A.A., O.T.L., R.Q.A., S.P., M.W., A.S.); Division of Imaging Sciences and Biomedical Engineering, Kings College London, BHF Centre of Research Excellence & Wellcome Trust - EPSRC Medical Engineering Centre & NIHR Biomedical Research Centre at Kings Health Partners, St. Thomas' Hospital, London, UK (M.E.A., U.B., A.P., A.J.W., T.S.); Radiology Department, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile (M.E.A.); Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital Solna, Stockholm, Sweden (T.R.); and Philips Healthcare, Guildford, UK (A.J.W.).
authors.forename: Thomas
authors.initials: T
authors.lastname: Renné
authors.affiliation: Academic Department of Surgery, Cardiovascular Division, Kings College London, BHF Centre of Research Excellence & NIHR Biomedical Research Centre at Kings Health Partners, St Thomas' Hospital, London, UK (P.S., B.M., J.H., A.S.P., C.E.E., K.M., S.P.G., A.A., O.T.L., R.Q.A., S.P., M.W., A.S.); Division of Imaging Sciences and Biomedical Engineering, Kings College London, BHF Centre of Research Excellence & Wellcome Trust - EPSRC Medical Engineering Centre & NIHR Biomedical Research Centre at Kings Health Partners, St. Thomas' Hospital, London, UK (M.E.A., U.B., A.P., A.J.W., T.S.); Radiology Department, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile (M.E.A.); Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital Solna, Stockholm, Sweden (T.R.); and Philips Healthcare, Guildford, UK (A.J.W.).
authors.forename: Sobath
authors.initials: S
authors.lastname: Premaratne
authors.affiliation: Academic Department of Surgery, Cardiovascular Division, Kings College London, BHF Centre of Research Excellence & NIHR Biomedical Research Centre at Kings Health Partners, St Thomas' Hospital, London, UK (P.S., B.M., J.H., A.S.P., C.E.E., K.M., S.P.G., A.A., O.T.L., R.Q.A., S.P., M.W., A.S.); Division of Imaging Sciences and Biomedical Engineering, Kings College London, BHF Centre of Research Excellence & Wellcome Trust - EPSRC Medical Engineering Centre & NIHR Biomedical Research Centre at Kings Health Partners, St. Thomas' Hospital, London, UK (M.E.A., U.B., A.P., A.J.W., T.S.); Radiology Department, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile (M.E.A.); Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital Solna, Stockholm, Sweden (T.R.); and Philips Healthcare, Guildford, UK (A.J.W.).
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Wiethoff
authors.affiliation: Academic Department of Surgery, Cardiovascular Division, Kings College London, BHF Centre of Research Excellence & NIHR Biomedical Research Centre at Kings Health Partners, St Thomas' Hospital, London, UK (P.S., B.M., J.H., A.S.P., C.E.E., K.M., S.P.G., A.A., O.T.L., R.Q.A., S.P., M.W., A.S.); Division of Imaging Sciences and Biomedical Engineering, Kings College London, BHF Centre of Research Excellence & Wellcome Trust - EPSRC Medical Engineering Centre & NIHR Biomedical Research Centre at Kings Health Partners, St. Thomas' Hospital, London, UK (M.E.A., U.B., A.P., A.J.W., T.S.); Radiology Department, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile (M.E.A.); Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital Solna, Stockholm, Sweden (T.R.); and Philips Healthcare, Guildford, UK (A.J.W.).
authors.forename: René M
authors.initials: RM
authors.lastname: Botnar
authors.affiliation: Academic Department of Surgery, Cardiovascular Division, Kings College London, BHF Centre of Research Excellence & NIHR Biomedical Research Centre at Kings Health Partners, St Thomas' Hospital, London, UK (P.S., B.M., J.H., A.S.P., C.E.E., K.M., S.P.G., A.A., O.T.L., R.Q.A., S.P., M.W., A.S.); Division of Imaging Sciences and Biomedical Engineering, Kings College London, BHF Centre of Research Excellence & Wellcome Trust - EPSRC Medical Engineering Centre & NIHR Biomedical Research Centre at Kings Health Partners, St. Thomas' Hospital, London, UK (M.E.A., U.B., A.P., A.J.W., T.S.); Radiology Department, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile (M.E.A.); Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital Solna, Stockholm, Sweden (T.R.); and Philips Healthcare, Guildford, UK (A.J.W.).
authors.forename: Tobias
authors.initials: T
authors.lastname: Schaeffter
authors.affiliation: Academic Department of Surgery, Cardiovascular Division, Kings College London, BHF Centre of Research Excellence & NIHR Biomedical Research Centre at Kings Health Partners, St Thomas' Hospital, London, UK (P.S., B.M., J.H., A.S.P., C.E.E., K.M., S.P.G., A.A., O.T.L., R.Q.A., S.P., M.W., A.S.); Division of Imaging Sciences and Biomedical Engineering, Kings College London, BHF Centre of Research Excellence & Wellcome Trust - EPSRC Medical Engineering Centre & NIHR Biomedical Research Centre at Kings Health Partners, St. Thomas' Hospital, London, UK (M.E.A., U.B., A.P., A.J.W., T.S.); Radiology Department, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile (M.E.A.); Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital Solna, Stockholm, Sweden (T.R.); and Philips Healthcare, Guildford, UK (A.J.W.).
authors.forename: Matthew
authors.initials: M
authors.lastname: Waltham
authors.affiliation: Academic Department of Surgery, Cardiovascular Division, Kings College London, BHF Centre of Research Excellence & NIHR Biomedical Research Centre at Kings Health Partners, St Thomas' Hospital, London, UK (P.S., B.M., J.H., A.S.P., C.E.E., K.M., S.P.G., A.A., O.T.L., R.Q.A., S.P., M.W., A.S.); Division of Imaging Sciences and Biomedical Engineering, Kings College London, BHF Centre of Research Excellence & Wellcome Trust - EPSRC Medical Engineering Centre & NIHR Biomedical Research Centre at Kings Health Partners, St. Thomas' Hospital, London, UK (M.E.A., U.B., A.P., A.J.W., T.S.); Radiology Department, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile (M.E.A.); Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital Solna, Stockholm, Sweden (T.R.); and Philips Healthcare, Guildford, UK (A.J.W.).
authors.forename: Alberto
authors.initials: A
authors.lastname: Smith
mesh_terms: D000818:Animals; D004730:Endothelium, Vascular / Q000293:injuries; D004912:Erythrocytes / Q000737:chemistry; D005342:Fibrinolysis / Q000502:physiology*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008026:Ligation; D008264:Macrophages / Q000502:physiology; D008279:Magnetic Resonance Imaging; D008297:Male; D013058:Mass Spectrometry; D008706:Methemoglobin / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency / Q000502:physiology; D010084:Oxidation-Reduction; D054390:Receptors, CCR2 / Q000172:deficiency / Q000502:physiology; D013997:Time Factors; D014682:Vena Cava, Inferior / Q000473:pathology; D020246:Venous Thrombosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology*
chemical_list: C515335:Ccr2 protein, mouse; D054390:Receptors, CCR2; D008706:Methemoglobin; D007501:Iron; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse
keywords: macrophages; magnetic resonance imaging; therapeutic thrombolysis; venous thrombosis